Smoking cessation may result in considerable body-weight gain, which often causes relapse or deters smokers from quitting. While leptin plays a key role in the control of body-weight, plasma leptin levels in cigarette smokers are significantly higher than those in non-smokers. Although cigarette smoking produces acute behavioral effects, its chronic effects on the central nervous system (CNS), which are associated with psychophysiological functions and neuroendocrinal changes, have not been investigated using neuroimaging. This may be partially due to the lack of suitable in vivo human models for directly examining the brain activity that is responsible for the regulation of those changes (e.g., biochemical signals such as the circulating insulin and leptin). The objective of this proposed project is to characterize brain activity that is associated with plasma leptin levels in chronic tobacco users. Specifically, we will use functional magnetic resonance imaging (fMRI) to compare the timing and localization of neural-hormonal interaction following food intake between smokers and non-smokers, with the focuses on the hypothalamus and its associated brain circuits using a novel dynamic approach developed by the PI. It is still not clear how leptin is regulated in the human brain; and much less is known about the interrelationship between peripheral leptin levels and the central anorexic signaling pathways. Thus, this proposed project may provide insight into the mechanisms relating chronic smoking to leptin, and the consequence of altered brain-leptin interaction in tobacco users. Two specific aims are to be accomplished. Aim 1: To test the hypothesis that tobacco smoking is associated with central leptin regulatory pathways localized in the hypothalamus, and this functional regulatory mechanism may be impaired in chronic cigarette smokers. We will tailor a fasting-eating fMRI paradigm to characterize the brain activity that is associated with plasma leptin and insulin during eating. Specifically, we will analyze the hypothalamic fMRI signal during a real-time transition from fasting hypoglycemia to normoglycemia attained by glucose ingestion so as to determine the impairment of brain-leptin interaction in chronic cigarette smokers. In the analysis, the leptin-associated brain activities will be compared among nonsmokers and chronic smokers (with and without cessation) by controlling for body weight, the post-cessation weight gain and relapse (for subjects with cessation), and other factors such as blood pressure and cholesterol. Aim 2: To test the hypothesis that leptin may modulate the activity among hedonic and rewarding brain circuits during the control of satiety signaling, and this modulation may be affected by tobacco smoking even when anorectic effects are reinforced. We will model the central anorectic signaling pathways involving leptin and insulin in chronic tobacco users, with a focus on the hypothalamic regions and their associated brain circuits involving the medial prefrontal cortex (including the orbitofrontal cortex), the insula, and the basal ganglia. The neural modeling will be accomplished by the task-dependent interregional covariance analysis of fMRI signal in fasting subjects (smokers and controls) during exposure to food-related emotional stimuli before and after eating.